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Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade
Jianhui Ma, … , Huangxuan Shen, Hongbing Zhang
Jianhui Ma, … , Huangxuan Shen, Hongbing Zhang
Published December 28, 2009
Citation Information: J Clin Invest. 2010;120(1):103-114. https://doi.org/10.1172/JCI37964.
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Research Article

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

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Abstract

The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated but not in well-differentiated human breast cancers. Both human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors with hyperactive mTOR due to tumor suppressor TSC1 or TSC2 deficiency exhibited enhanced STAT3/p63/Notch signaling. Furthermore, tumorigenic potential of cells with uncontrolled mTOR signaling was suppressed by Notch inhibition. Our data therefore suggest that perturbation of cell differentiation by augmented Notch signaling might be responsible for the underdifferentiated phenotype displayed by certain tumors with an aberrantly activated RTK/PI3K/AKT/mTOR pathway. Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling.

Authors

Jianhui Ma, Yan Meng, David J. Kwiatkowski, Xinxin Chen, Haiyong Peng, Qian Sun, Xiaojun Zha, Fang Wang, Ying Wang, Yanling Jing, Shu Zhang, Rongrong Chen, Lianmei Wang, Erxi Wu, Guifang Cai, Izabela Malinowska-Kolodziej, Qi Liao, Yuqin Liu, Yi Zhao, Qiang Sun, Kaifeng Xu, Jianwu Dai, Jiahuai Han, Lizi Wu, Robert Chunhua Zhao, Huangxuan Shen, Hongbing Zhang

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Figure 2

mTOR is a positive regulator of Notch signaling.

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mTOR is a positive regulator of Notch signaling.
(A) WT, Tsc2–/–, and Pt...
(A) WT, Tsc2–/–, and Pten–/– MEFs and WT MEFs transduced with the retroviruses for myristoylated AKT1 (myrAKT1) in pLXIN-hyg or its control vector pLXIN-hyg (V) were treated with or without 10 nM rapamycin for 24 hours and then subjected to immunoblotting for Hes1 and p-S6 (Ser235/236). (B) mTOR and Notch signaling were assessed by immunoblotting in age-matched normal kidneys and 2 kidney tumors from Tsc2del3/+ mice. (C) Left: Hes1 promoter reporter luciferase assay for WT and Tsc1–/– MEFs treated with or without 10 nM rapamycin for 24 hours. The relative Hes1-luciferase activity (firefly luciferase activity/Renilla luciferase activity) is shown. Right: Quantitative real-time RT-PCR for relative Hes1 mRNA from WT and Tsc2–/– MEFs. Values are the mean ± SD of triplicate samples. *P < 0.05. (D) WT, Tsc2–/–, and Pten–/– MEFs and WT MEFs transduced with the retroviruses for AKT1E17K (mutAKT) in pLXIN-hyg or its control vector pLXIN-hyg (V) were treated with or without 10 nM rapamycin for 24 hours and then subjected to immunoblotting for active Notch1 (NICD) and p-S6. (E) WT MEFs transduced with the retroviruses for NICD in pMig (pMig-ICN1) (NICD) or its control vector pMIG (V) in the presence or absence of 10 nM rapamycin for 24 hours and then subjected to immunoblotting for p-S6, NICD, and Hes1.

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